Synthetic methods for the preparation of ARQ 501 (β-Lapachone) human blood metabolites

Yang, Rui‐Yang; Kizer, Darin; Wu, Hui; Volckova, Erika; Miao, Xiaofei; Ali, Sk Ajim; Tandon, Manish; Savage, Ronald E.; Chan, Thomas C. K.; Ashwell, Mark A.

doi:10.1016/j.bmc.2008.03.073

Cited by 54 publications

(32 citation statements)

References 7 publications

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“…Such oxidation of iron is consistent with the known reactive oxygen species (ROS) generation by naphthoquinones (4). The mechanism by which β-lap converts the ferrous ion of hemoglobin to methemoglobin is currently unclear, but is hypothesized to involve metabolism of the drug by enzymes in RBCs (31). β-Lap can be metabolized into at least six distinct metabolites after incubation with RBCs (31), and ROS resulting from this metabolism may convert hemoglobin to methemoglobin.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism by which β-lap converts the ferrous ion of hemoglobin to methemoglobin is currently unclear, but is hypothesized to involve metabolism of the drug by enzymes in RBCs (31). β-Lap can be metabolized into at least six distinct metabolites after incubation with RBCs (31), and ROS resulting from this metabolism may convert hemoglobin to methemoglobin. Research is underway to investigate this mechanism and the in vivo consequences, as methemoglobinemia can lead to a decreased ability to carry oxygen, resulting in tissue hypoxia (28).…”

Section: Discussionmentioning

confidence: 99%

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β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

et al. 2010

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Lung cancer is the leading cause of cancer-related deaths with current chemotherapies lacking adequate specificity and efficacy. β-Lapachone (β-lap) is a novel anticancer drug that is bioactivated by NAD(P)H:quinone oxidoreductase 1, an enzyme found specifically overexpressed in non-small cell lung cancer (NSCLC). Herein, we report a nanotherapeutic strategy that targets NSCLC tumors in two ways: (a) pharmacodynamically through the use of a bioactivatable agent, β-lap, and (b) pharmacokinetically by using a biocompatible nanocarrier, polymeric micelles, to achieve drug stability, bioavailability, and targeted delivery. β-Lap micelles produced by a film sonication technique were small (∼30 nm), displayed core-shell architecture, and possessed favorable release kinetics. Pharmacokinetic analyses in mice bearing subcutaneous A549 lung tumors showed prolonged blood circulation (t 1/2 , ∼28 h) and increased accumulation in tumors. Antitumor efficacy analyses in mice bearing subcutaneous A549 lung tumors and orthotopic Lewis lung carcinoma models showed significant tumor growth delay and increased survival. In summary, we have established a clinically viable β-lap nanomedicine platform with enhanced safety, pharmacokinetics, and antitumor efficacy for the specific treatment of NSCLC tumors. Cancer Res; 70(10); 3896-904. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

et al. 2010

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“…, structures ( 3 ) and ( 4 )) should help create a spectral data bank, to understand the fragmentation and reactivity of new derivatives of these compounds. In addition, the use of mass spectrometry for the elucidation of in vitro and in vivo metabolites from lapachol has been demonstrated, and α‐ and β‐lapachone were the major secondary metabolites observed in these studies . To date, only electron ionization (EI‐MS) results are available for compounds ( 1 )–( 4 ) .…”

mentioning

confidence: 99%

“…The major EI fragments ions occur at m/z 130 and 102, and the main difference between ( 1 ) +• and ( 2 ) +• is the relative intensity of these ions. Recent studies on the metabolism of ( 4 ) by ESI‐MS/MS and high‐resolution analysis have helped describe its metabolites in vitro . However, the authors did not elucidate the dissociation mechanisms, and there is a need for more advanced analysis.…”

mentioning

confidence: 99%

Electronic structure and gas‐phase chemistry of protonated α‐ and β‐quinonoid compounds: a mass spectrometry and computational study

Vessecchi

Emery

Lopes

et al. 2013

Rapid Comm Mass Spectrometry

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MS/MS studies on lapachol isomers (α- and β-lapachone) will facilitate the interpretation of the liquid chromatography (LC)-MS/MS analysis of new metabolites. MS/MS data on the 1,4-naphthoquinone, 1,2-naphthoquinone, α-lapachone and β-lapachone core will help characterize new derivatives from in vitro/in vivo metabolism studies in complex matrices. The product ions revealed the major fragmentation mechanisms and these ions will serve as diagnostic ions to identify each studied compound.

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“…1 ARQ-501 is also effective against human ovarian cancer and prostrate cancer xenografs in mice. 2 Tetralone 1 can also be used in the synthesis of previously reported tetralone 3 2 and tetralone 4 3.…”

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confidence: 99%

Transformation of 5-Methoxy-1-Tetralone into 8-Methoxy-1-Tetralone

Banerjee

Bedoya

Adherían

et al. 2010

Journal of Chemical Research

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The transformation of 1-hydroxy-5-methoxtetralin into 4-hydroxy-8-methoxy-1-tetralone was accomplished in three steps (benzoylation, oxidation and alkaline hydrolysis). Treatment of the corresponding ketotosylate with sodium iodide and zinc dust in dimethoxyethane yielded the 8-methoxy-1-tetralone in 22% yield. The ketotosylate also underwent detosylation with sodium cyanoborohydride but afforded tetraol in 45% yield which on oxidation was converted into the required tetralone in 87% yield.

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Synthetic methods for the preparation of ARQ 501 (β-Lapachone) human blood metabolites

Cited by 54 publications

References 7 publications

β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

β-Lapachone Micellar Nanotherapeutics for Non–Small Cell Lung Cancer Therapy

Electronic structure and gas‐phase chemistry of protonated α‐ and β‐quinonoid compounds: a mass spectrometry and computational study

Transformation of 5-Methoxy-1-Tetralone into 8-Methoxy-1-Tetralone

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